We propose to synthesize a series of planar ring-expanded (5:7- and 5:8- fused) nucleosides shown in Chart I, and their N4-alkyl derivatives where possible, and screen them along with their heterocyclic aglycons against HIV in vitro. Those nucleosides that show promise in the in vitro HIV assay will be further converted to their corresponding 5'-triphosphate derivatives and biochemically screened along with their heterocyclic aglycons for substrate/inhibition against HIV reverse transcriptase as well as against a mammalian DNA polymerase for assessment of specificity. Our secondary goals include performing mechanistic investigation of DNA incorporation of the most promising compound from the above screening assays, employing radiolabeling techniques. The other secondary goals are to explore acid-base properties, tautomerism, conformational characteristics, base-pairing and stacking interactions, as well as helical/double-helical conformation and stability of selected nucleosides, nucleotides, and polynucleotides that emerge promising from the above screening studies. Our long-term goals include performing pharmacokinetic and pharmacodynamic studies of the most promising compounds from the above investigations to assess their pre-clinical efficacy.